CN105106959B - Application and a kind of pharmaceutical composition of the cordycepin in the drug of preparation and radiotherapy and/or chemotherapy synergistic treatment tumour - Google Patents
Application and a kind of pharmaceutical composition of the cordycepin in the drug of preparation and radiotherapy and/or chemotherapy synergistic treatment tumour Download PDFInfo
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Abstract
The present invention relates to field of medicaments, disclose cordycepin and are preparing and the application in the drug of radiotherapy and/or chemotherapy synergistic treatment tumour, wherein the cordycepin has structure shown in formula (1)；The invention also discloses a kind of and radiotherapy and/or the pharmaceutical compositions of chemotherapy synergistic treatment tumour, wherein the pharmaceutical composition includes active constituent, and the active constituent includes at least one of daunorubicin, dactinomycin D, adriamycin and cordycepin.Cordycepin of the present invention has the advantages that functioning efficiency height and Small side effects in the application in preparing the drug with radiotherapy and/or chemotherapy synergistic treatment tumour.
Description
Technical field
The present invention relates to field of medicaments, and in particular, to cordycepin is being prepared and radiotherapy and/or chemotherapy synergistic treatment tumour
Drug in application and a kind of with radiotherapy and/or the pharmaceutical composition of chemotherapy synergistic treatment tumour.
Background technology
The main means of Current therapeutic malignant tumour include radiation cure and chemotherapy, and clinically there are about 90% evils
Property tumour need to carry out radiotherapy and/or chemotherapy.
So-called chemotherapy is mainly the drug therapy cancer that use can kill cancer cell, due to cancer cell and normal cell
Maximum difference is in the cell division of cancer cell and cell growth compared with normal cell, so the action principle of anticancer drug is logical
It is often to inhibit the growth of cancer cell by the mechanism of the division of interference cell, such as the duplication of DNA is inhibited either to prevent to contaminate
The separation of colour solid.However, most of chemotherapeutics selectivity is all very low, they can also be killed while killing cancer cell into
The fissional normal tissue cell of row, thus can usually injure and need into line splitting to maintain the health tissues of normal function,
The patient that usually immunity can be made weaker in this way situation after receiving chemotherapy becomes worse.And radiation cure is also referred to as put
It treats, radiation-therapy, is that cancer cell is killed by using radiation, reduces tumour.Radiotherapy can via External radiotherapy or
In vivo close to radiotherapy.Since the growth and division of cancer cell are all fast compared with normal cell, the something lost of cell is destroyed by radiation
Substance is passed, cell growth or division can be prevented, and then control the growth of cancer cell.But the effect of radiotherapy is only capable of limiting to
In the region for receiving irradiation.The target of radiotherapy is then to destroy all cancer cells as far as possible, while reducing to the greatest extent pair
The influence of neighbouring health tissues.But in clinical practice, in order to destroy all cancer cells as much as possible, neighbour can usually be killed
Nearly more normal cell, so that the weaker cancer patient of immunity is difficult to recover from the injury of radiotherapy.
As a double-edged sword, radiation and chemotherapy is while effectively treatment tumour, also to the multiple organs of human body and system
Generate huge injury.In these injuries, most common is exactly bone marrow suppression.Bone marrow suppression is to directly affecting for human body
The generation of various cells especially leucocyte in blood is caused to reduce.Index of the leucocyte as immunity of organisms, its function
Exactly kill or inhibit to intrude into the generation of internal various bacteriums, virus and unwanted cells.Due to white caused by bone marrow suppression
Leukopenia causes great damage to the immunity of patient.Chemicotherapy is at once to the injury that body immunity generates in the recent period
, it is threat to life sometimes, each cancer patient by both methods treatment can have deep impression, seldom
Within the scope of capable of having tumour patient leucocyte during treatment to have been at normal, common situation is many patients due to putting
It treats and chemotherapy has destroyed its multiple tracks and defence line is immunized so that patient is finally since hypoimmunity cannot resist common bacterium and disease
Poison infection and it is dead.
Therefore, it is that treatment of cancer is successful that each road immunity defence line of patient how is protected in the therapeutic process of cancer
It is crucial.
In order to reduce the injury for being difficult to reverse brought to cancer patient due to radiation and chemotherapy, prior art generally use
Carrying out radiotherapy and/or while chemotherapy or give before and after radiotherapy and/or chemotherapy cancer patient some enhancings immune
The drug of ability, the common drug for enhancing cancer patient's immunocompetence mainly have：Glucocorticoid, scutelloside and winter
The extraction mixture etc. of worm summer grass.However, these drug generally existings can bring different degrees of side effect and work to patient
With inefficient defect.
Therefore, there is an urgent need for find that a kind of therapeutic efficiency that can overcome the prior art is low and the high defect of side effect at present
Drug so that cancer patient can maintain stronger immunocompetence in receiving radiotherapy and/or chemotherapy process, to reduce or
Avoid the injury of radiotherapy and/or chemotherapy process to cancer patient.
Invention content
The purpose of the present invention is overcome the method for using the prior art to provide raising to receive the cancer trouble of radiotherapy and/or chemotherapy
The defect that existing efficiency is low when the immunocompetence of person and side effect is big provides cordycepin and is preparing and radiotherapy and/or chemotherapy
Application in the drug of synergistic treatment tumour and the pharmaceutical composition of a kind of and radiotherapy and/or chemotherapy synergistic treatment tumour.
To achieve the goals above, on the one hand, the present invention provides cordycepin and preparing and radiotherapy and/or chemotherapy synergistic treatment
Application in the drug of tumour, wherein the cordycepin has structure shown in formula (1),
On the other hand, the present invention also provides a kind of with radiotherapy and/or the pharmaceutical composition of chemotherapy synergistic treatment tumour,
In, which includes active constituent, the active constituent by daunorubicin, dactinomycin D, adriamycin, bleomycin,
Mitomycin, mustargen, Chlorambucil, cyclophosphamide, Ismipur, 6- thioguanines, cytarabine, 5 FU 5 fluorouracil,
Floxuridine, methotrexate (MTX), colchicin, vincristine, vinblastine, etoposide, erlotinib Hydrochloride piece, cis-platinum, Japanese yew
Alcohol, docetaxel, vinorelbine, elemene, hydroxycamptothecin, polyenoid purple pole alcohol, gemcitabine, Hycamtin and Irinotecan
At least one of and cordycepin composition.
Cordycepin of the present invention has when preparing with application in the drug of radiotherapy and/or chemotherapy synergistic treatment tumour
The advantages of having functioning efficiency high and Small side effects, cancer patient is within the period for receiving radiotherapy and/or chemotherapy or and optionally
Ground is before and after receiving the period of radiotherapy and/or chemotherapy using can significantly reduce radiation and chemotherapy when cordycepin to body
Injury, contributes to cancer patient to restore immunocompetence after receiving radiotherapy and/or chemotherapy caused by body.
Cordycepin of the present invention as with the pharmaceutical composition of radiotherapy and/or chemotherapy synergistic treatment tumour activity at
/ mono- in use, can be by the active constituent and optional common medicinal supplementary material hybrid modulation at usually used various doses
Type, such as tablet, capsule, pill, injection, sustained release preparation, controlled release preparation, as of the present invention and radiotherapy and/or change
The pharmaceutical composition for treating synergistic treatment tumour uses.
Other features and advantages of the present invention will be described in detail in subsequent specific embodiment part.
Specific implementation mode
The specific implementation mode of the present invention is described in detail below.It should be understood that described herein specific
Embodiment is merely to illustrate and explain the present invention, and is not intended to restrict the invention.
On the one hand, the present invention provides cordycepins in the drug of preparation and radiotherapy and/or chemotherapy synergistic treatment tumour
Using, wherein the cordycepin has structure shown in formula (1),
In the present invention, it should be strongly noted that the cordycepin is swollen in preparation and radiotherapy and/or chemotherapy synergistic treatment
It is prepared by application that the application in the drug of tumor includes cordycepin in preparing the drug with radiotherapy synergistic treatment tumour, cordycepin
With in the drug of chemotherapy synergistic treatment tumour application and cordycepin preparing and the medicine of radiation and chemotherapy synergistic treatment tumour
Application in object.
In the present invention, the cordycepin is also known as 3'-Deoxyadenosine (3-deoxyadenosine).
(also it is to be cooperateed with radiotherapy and/or chemotherapy in the drug containing the cordycepin in application of the present invention
Treat the drug of tumour) in, the content of the cordycepin is 10-100 weight %；Preferably 50-100 weight %；More preferably
100 weight %.
In application of the present invention, to the drug for the chemotherapy, there is no particular limitation, particularly preferred feelings
Under condition, it was found by the inventors of the present invention that the drug of used chemotherapy include daunorubicin, dactinomycin D, adriamycin, it is rich come it is mould
Element, mitomycin, mustargen, Chlorambucil, cyclophosphamide, Ismipur, 6- thioguanines, cytarabine, 5- fluorine urine are phonetic
Pyridine, floxuridine, methotrexate (MTX), colchicin, vincristine, vinblastine, etoposide, erlotinib Hydrochloride piece, cis-platinum and
When at least one of taxol, it can more significantly reduce radiation and chemotherapy to body using cordycepin of the present invention
Caused by injure, contribute to cancer patient to restore immunocompetence after receiving radiotherapy and/or chemotherapy.
Application according to the present invention, the drug containing the cordycepin are preferably 0.1Gy to 100Gy with irradiation dose
Between Patients During Radiotherapy collaboration use.
In application of the present invention, the tumour may include cutaneum carcinoma, nasopharyngeal carcinoma, breast cancer, cervical carcinoma, oesophagus
At least one of cancer, colon cancer, prostate cancer, oophoroma, lymph cancer, liver cancer, lung cancer, leukaemia and gastric cancer.
Application according to the present invention, the drug containing the cordycepin can be in the weeks for receiving radiotherapy and/or chemotherapy
In phase, 1-180 days before receiving the period of radiotherapy and/or chemotherapy it is interior and the period for receiving radiotherapy and/or chemotherapy it
It is used at least one period in 1-180 days afterwards.Particularly, in the present invention, radiotherapy and/or the chemotherapy of receiving
Period refer to from starting to receive radiotherapy and/or chemotherapy to the time range in accordance with doctor's advice radiotherapy and/or end of chemotherapy, generally according to
The tumor presence of cancer patient, doctor can arrange radiotherapy twice either more than twice, and so this is twice or more than twice
Radiotherapy belongs to the same period for receiving radiotherapy；For the period of chemotherapy, can specifically it be explained as follows：From abiding by
According to doctor's advice start to take either injection chemotherapeutics to a cycle for cutting out or injecting chemotherapeutics and be known as chemotherapy.It is special
Not, some cancer patients receive 2 months or more check discovery cancer cells after radiotherapy and/or chemotherapy in stopping a large amount of increasings
Add and must not be no longer secondary when receiving radiotherapy and/or chemotherapy, the radiotherapy and/or chemotherapy that start again at belong to another period.
Under preferable case, in an application of the invention, the drug containing the cordycepin is receiving radiotherapy and/or chemotherapy
In period, in 1-100 days before receiving the period of radiotherapy and/or chemotherapy and in the period for receiving radiotherapy and/or chemotherapy
It is used in 1-150 days later.
The dosage of cordycepin depends on many factors in application of the present invention, such as cancer patient suffers from cancer kind
Class and severity, gender, age, weight and the individual reaction of patient, administration route and administration number of times etc., therefore, this
The dosage of invention can have a greater change range.Under preferable case, relative to the drug to be used containing the cordycepin
The dosage of every kg weight of patient, the drug containing the cordycepin can be 0.001-1000mg.
On the other hand, the present invention also provides a kind of with radiotherapy and/or the pharmaceutical composition of chemotherapy synergistic treatment tumour,
In, which includes active constituent, the active constituent by daunorubicin, dactinomycin D, adriamycin, bleomycin,
Mitomycin, mustargen, Chlorambucil, cyclophosphamide, Ismipur, 6- thioguanines, cytarabine, 5 FU 5 fluorouracil,
Floxuridine, methotrexate (MTX), colchicin, vincristine, vinblastine, etoposide, erlotinib Hydrochloride piece, cis-platinum, Japanese yew
Alcohol, docetaxel, vinorelbine, elemene, hydroxycamptothecin, polyenoid purple pole alcohol, gemcitabine, Hycamtin and Irinotecan
At least one of and cordycepin composition, the cordycepin have formula (1) shown in structure,
Can also include conventional use of various auxiliary materials in the art in pharmaceutical composition of the present invention, such as can be with
Including cosolvent, buffer, pH adjusting agent, colorant fragrance, corrigent, sweetener or other materials.
In the present invention, described pharmaceutical composition can be prepared according to various methods known in the art.For this hair
When bright purpose, if it is desired, active constituent of the present invention and one or more solids and/or liquid medicine can be assigned
Shape agent and/or auxiliary material combine, and the appropriate use form or dosage form that can be used as that people's medicine uses is made.
In the present invention, the pharmaceutical composition with radiotherapy and/or chemotherapy synergistic treatment tumour, which can be prepared into, has
The preparation of a variety of dosage forms, such as may include：Tablet, capsule, pill, injection, sustained release preparation, controlled release preparation etc..
In order to which the above-mentioned common formulations enumerated are made in unit dosage forms for administration, can be widely used well known in the art each
Kind carrier, the citing about carrier is, such as diluent and absorbent, such as starch, dextrin, calcium sulfate, lactose, mannose, sugarcane
Sugar, sodium chloride, glucose, urea, calcium carbonate, white bole, microcrystalline cellulose, alumina silicate etc.；Wetting agent and adhesive, as water,
Glycerine, polyethylene glycol, ethyl alcohol, propyl alcohol, starch slurry, dextrin, syrup, honey, glucose solution, mucialga of arabic gummy, gelatine size, carboxylic
Sodium carboxymethylcellulose pyce, lac, methylcellulose, potassium phosphate etc.；Disintegrant, such as dry starch, alginate, agar powder etc.；
Disintegration inhibitor, such as cocoa butter, hydrogenated oil and fat；Sorbefacient, such as quaternary ammonium salt, lauryl sodium sulfate；Lubricant is such as sliding
Mountain flour, silica etc..
Pharmaceutical composition of the present invention can be administered in a unit, and administration route can be intestinal canal administration form
Either parenteral administration is such as oral, muscle, subcutaneous, nasal cavity, mucous membrane of mouth, skin, peritonaeum or rectum.
The administration route of pharmaceutical composition of the present invention can also be drug administration by injection, and injection includes intravenous injection, flesh
Meat injection, hypodermic injection, intracutaneous injection and acupoint injection therapy etc..
In the pharmaceutical composition of of the present invention and radiotherapy and/or chemotherapy synergistic treatment tumour, relative to the work
The total weight of property ingredient, the content of the cordycepin can be 0.001-80 weight %.
Under preferable case, in the pharmaceutical composition of of the present invention and radiotherapy and/or chemotherapy synergistic treatment tumour, phase
For the total weight of the active constituent, the content of the cordycepin is 0.01-50 weight %.
In the present invention, to the source of the cordycepin, there is no particular limitation, as long as the purity of used cordycepin
It is 99% or more.Method synthesis obtains or from commercially available cordycepin of the present invention according to prior art.
The present invention will be described in detail by way of examples below.In following embodiment, in the feelings being not particularly illustrated
Under condition, used a variety of materials are all from commercially available.Wherein, the weight of the mouse be each group mouse Weight averages ±
Standard deviation (g).Used cordycepin is commercially available from, and it is 99.9% to purify to purity by column chromatography method.
Toxicity test
Acute toxicity test：
Experimental animal：Cleaning grade Kunming mouse 20, half male and half female, weight 18-22g, by Military Medical Science Institute's reality
Animal center offer is provided.
Animal feeding environment：SPF grades, room temperature is (20.0-22.5) DEG C, and relative humidity is (54.4-68.4) %RH, group's cage
Raising, 10/cage.
Feed resource：Military Medical Science Institute's Experimental Animal Center；Feed Manufacturing credit number：Cleaning grade, SCXK- (army)
2007-005。
Experimental method：Experimental animal adapts to environment 4 days, selects healthy adult mouse 20, half male and half female, dose design female
For 10.0g/kg mouse, male is 10.0g/kg mouse, and cordycepin aqueous solution (1g/ is given by 0.2mL/10g mouse well head gavages
ML), for 24 hours in gavage twice.Animal overnight fasting before gavage, free water.Normal diet is given after gavage, is observed 14 days, note
Record poisoning sign and death condition.
As a result, it has been found that within the above-mentioned observation period (14 days), experimental animal has no poisoning sign, well-grown, gross anatomy
No abnormality seen.
The oral MTD of female mice is more than 10.0g/kg mouse；The oral MTD of male mice is more than 10.0g/kg mouse.
Sentenced according to acute toxicity grading criteria in toxicological evaluation of food safety procedure and method (GB15193-2003)
Fixed, the true border of cordycepin chmice acute Oral toxicity is nontoxic.
Chronic toxicity test：
Pre-treating method：Low, middle dose group：100g, 1000g cordycepin are weighed respectively, add basic fabric to 20kg, stirring
Uniformly.High dose group weighs cordycepin 2000g, casein 400g, adds basic fabric to 20kg, stir evenly.
Experimental animal：Cleaning grade Wistar kinds rat 80, half male and half female, weight 61-83g, by Military Medical Science Institute
Experimental Animal Center provides.
Animal feeding environment：SPF grades, room temperature is (20.0-24.8) DEG C, and relative humidity is (43.9-49.8) %RH, single cage
Raising.
Feed resource：Military Medical Science Institute's Experimental Animal Center；Feed Manufacturing credit number：Cleaning grade, SCXK- (army)
2007-005。
Administering mode：Mix feed feeding.
Dose design：The maximum ratio that high dose group dose design is carried that family by cordycepin in feed is 10%, 90 day
Feed food ration by weight 8% conversion, be 8g/kg rats, in, low dose group 4.0,0.4g/kg rats.It is negative right separately to set
According to group.
Operating procedure：Select weanling rat 80, half male and half female to be randomly divided into 4 groups by weight, i.e., negative control group,
Three 0.4g/kg rats, 4.0g/kg rats and 8g/kg rats dosage groups.It according to dosage designs within continuous 90 days and cordycepin is mixed into base
It is fed in plinth fabric, control group gives conventional foundation fabric.
During experiment, animal freely ingests and drinks water, and observes and records the general performance, behavior, poisoning body of animal daily
It seeks peace death condition.
Statistical disposition is carried out to data using SPSS12.0 softwares.
As a result：
Under this experiment condition, low dose group cordycepin make the weight of animals decline, weight gain decline, weekly food-intake and
Total food-intake reduces, has an impact to individual all food utilizations and buck total food utilization rate.To 45 days, 90 days low dosages
Group blood routine and classification leucocyte are without influence；Have an impact to 45 days, 90 days biochemical indicators, but abiology meaning, low dose
The reduction consideration of amount group total protein and albumin is related with food-intake reduction；Low dose group male and female rat prothrombin time, work
Change partial thromboplastin time, there are no significant for difference compared with the control group for thrombin time, and low dose group male rat blood is small
Plate is substantially reduced, but abiology meaning.Cordycepin has different degrees of influence to low dose group organ wet weight and dirty/body ratio, examines
Consider, abiology meaning related with weight loss.Low dose group does not occur significant notable group relevant with cordycepin toxicity
Knit pathological change.
Embodiment 1
The present embodiment illustrates that cordycepin of the present invention is preparing the drug with chemotherapy synergistic treatment lung cancer in cellular level
In application, in particular：
The method culture lung carcinoma cell provided using CN103272216A, specially：By human lung adenocarcinoma A-549 cells according to
Conventional culture methods are activated and are passed on, wherein culture medium is the dual anti-+ 10%FBS of RPMI1640+1% (in RPMI1640
Penicillin, streptomysin mixed liquor and fetal calf serum (FBS) are added in (Invitrogen, 11875-093), the above two is made finally to contain
It is the culture solution that 10 volume % are obtained that amount, which is the content of 1 volume %, FBS).
Made using MTT method (MTT) detection cordycepin and the synergistic treatment of chemotherapy on human adenocarcinoma of lung A-549 cells
With.The specific method is as follows：Select P8 for human lung adenocarcinoma A-549 cells, respectively with every hole 7 × 103A/mL human lung adenocarcinomas A-549
Cell inoculation after cell is completely adherent, selects 40 hole cells to be divided into 8 groups, respectively high dose and chemotherapy at random in 96 orifice plates
Group, middle dosage and chemotherapy group, low dosage and chemotherapy group, the non-chemotherapy group of high dose, the non-chemotherapy group of middle dosage, the non-chemotherapy of low dosage
Group, chemotherapeutical control group and control group, every group of 5 hole cells.
The culture solution and 5mg of the cordycepin containing 90 μ g/mL of 200 μ L are added in high dose and every hole cell of chemotherapy group
Erlotinib Hydrochloride piece；
The culture solution of the cordycepin containing 90 μ g/mL of 200 μ L is added in every hole cell of the non-chemotherapy group of high dose；
The culture solution and 5mg of the cordycepin containing 60 μ g/mL of 200 μ L are added in every hole cell of middle dosage and chemotherapy group
Erlotinib Hydrochloride piece；
The culture solution of the cordycepin containing 60 μ g/mL of 200 μ L is added in every hole cell of the non-chemotherapy group of middle dosage；
The culture solution and 5mg of the cordycepin containing 30 μ g/mL of 200 μ L are added in low dosage and every hole cell of chemotherapy group
Erlotinib Hydrochloride piece；
The culture solution of the cordycepin containing 30 μ g/mL of 200 μ L is added in every hole cell of the non-chemotherapy group of low dosage；
The serum-free medium of 200 μ L is added in every hole cell of control group.
It adds after culture solution cultivates 72h at 37 DEG C, the MTT working solutions (5mg/ that sterile water is prepared of 200 μ L is added per hole
MLMTT solution：Serum-free medium=1：9 (volume ratios)) it is protected from light and continues to cultivate 4h, it is careful to inhale the cell culture fluid abandoned in hole,
200 μ L dimethyl sulfoxides (DMSO), concussion are added to be incubated 10min, crystal is made fully to dissolve per hole.With microplate reader in 560nm wavelength
Place surveys absorbance (OD), with the cell survival rate of control group for 100%, calculates survival rate (each group cell of remaining each group cell
Survival rate=OD (to be evaluated group)/OD (control group) × 100%) and each group cell the apoptosis rate (apoptosis of each group cell
The survival rate of rate=100%- each group cells).Described to be evaluated group include high dose and chemotherapy group, it is middle dosage and chemotherapy group, low
Dosage and the non-chemotherapy group of chemotherapy group, high dose, the non-chemotherapy group of middle dosage, the non-chemotherapy group of low dosage and chemotherapeutical control group.
Test independent samples t test processing statistics of all data using SPSS12.0 statistical softwares.Each group cell withers
It is as shown in table 1 to die rate.
Wherein, above-mentioned serum-free medium is RPMI1640+1% dual anti-, and the above-mentioned culture solution containing cordycepin is respectively
To the dual anti-middle cordycepins that corresponding amount is added of RPMI1640+1%.RPMI1640+1% dual anti-is in RPMI1640
(penicillin 10000U/mL, streptomysin are for addition penicillin and streptomysin mixed liquor in (Invitrogen, 11875-093)
10000 μ g/mL), make the serum-free medium that the final content of the two is 1 volume %.
Mtt assay measurement result is as shown in table 1.The result shows that using cordycepin to be assisted with chemotherapeutics on a cellular level
When with treatment lung carcinoma cell, the apoptosis rate of cell can reach 85.2-97.2%, specifically, use high agent of the present invention
When the cordycepin of amount is carried out at the same time with chemotherapy, Increase Apoptosis of Lung Cancer Cells rate is 97.2%；Use the worm of middle dosage of the present invention
When careless element is carried out at the same time with chemotherapy, Increase Apoptosis of Lung Cancer Cells rate is 91.1%；Using low dosage of the present invention cordycepin with
When chemotherapy is carried out at the same time, Increase Apoptosis of Lung Cancer Cells rate is 85.2%.And under the same conditions, lung carcinoma cell only receives chemotherapy without making
When with cordycepin, Increase Apoptosis of Lung Cancer Cells rate is only 43.1%.And by the non-chemotherapy group of high dose, the non-chemotherapy group of middle dosage and low dose
When measuring the result of non-chemotherapy group and being compared respectively with the result of high dose chemotherapy group, middle dosage chemotherapy group and low-dosage chemotherapy group
As can be seen that lung carcinoma cell only receives the cordycepin of high dose of the invention, middle dosage and low dosage without being carried out at the same time chemotherapy
When, the apoptosis rate abiology meaning of lung carcinoma cell, the effect much uses cordycepin and chemotherapeutic not as good as the collaboration of the present invention
The effect of object, the present embodiment illustrate that the cordycepin of the present invention has with the drug for the treatment of lung cancer from cellular level and cooperate with work
With.
Table 1
| Apoptosis rate (%) | |
| High dose chemotherapy group | 97.2 |
| Middle dosage chemotherapy group | 91.1 |
| Low-dosage chemotherapy group | 85.2 |
| The non-chemotherapy group of high dose | - |
| The non-chemotherapy group of middle dosage | - |
| The non-chemotherapy group of low dosage | - |
| Chemotherapeutical control group | 43.1 |
| Control group | - |
Embodiment 2
The present embodiment illustrates that cordycepin of the present invention is preparing the medicine with chemotherapy synergistic treatment colon cancer in animal level
Application in object, in particular：
Modeling：Using the prior art (" a kind of duplication of the relevant model of colon cancer of colitis ", Li Yuhua etc., China of the world
People digests magazine, 2007,15 (3)：234-239) method provided makes mouse junction cancer model, specially：To waiting for modeling mouse
Implement the Dimethylhydrazine (DMH) of intraperitoneal injection 15mg/kg after 1 week, then gives mouse and drink the Dextran sodium sulfate containing 20g/L
(DSS) water one week, it is then normal to feed 20 weeks, it then randomly selects 10 modeling mouse and puts to death, discovery reaches at cancer rate
100%, conclusion is modeling success.
50 (18-20g) above-mentioned model of colon cancer mouse is taken, in intraperitoneal injection 5 FU 5 fluorouracil (dosage 150mg/
Kg weight) grouping (every group of 10 mouse) at random afterwards, it is respectively designated as high dose group, middle dose group, low dose group, control group 1
With control group 2, the normal mouse of 10 (18-20g) non-modelings is separately taken, Normal group is named as；And separately take 30 (18-
20g) model of colon cancer mouse is divided into 3 groups, is respectively designated as control group 3, control group 4 and control group 5.
Disposition is as follows：Model mice in control group 3, control group 4 and control group 5 does not give intraperitoneal injection 5- fluorine urine
Pyrimidine gives the high dose group and control group 3 50 microlitres of the cordycepin aqueous solution of intraperitoneal injection 90mg/kg weight, right
The middle dose group and control group 4 give 50 microlitres of the cordycepin aqueous solution of intraperitoneal injection 60mg/kg weight and to described
Low dose group and control group 5 give 50 microlitres of the cordycepin aqueous solution of intraperitoneal injection 30mg/kg weight, are given to control group 1
50 microlitres of waters for injection are injected intraperitoneally, control group 2 and Normal group are not processed, according to above-mentioned identical method, daily
Once in the morning and once at night (totally 2 times) give note in high dose group, middle dose group, low dose group, control group 1 and 2 mouse peritoneal of control group
5 FU 5 fluorouracil (dosage is 150mg/kg weight) is penetrated, also, each primary in the morning, afternoon and evening daily according to the identical method of above-mentioned difference
(totally 3 times) give injection in high dose group, middle dose group, low dose group, control group 3, control group 4 and 5 mouse peritoneal of control group
50 microlitres of cordycepin aqueous solution gives 50 microlitres of 1 intraperitoneal injection water for injection of control group, to control group 2 and Normal group
It is not processed.Experiment terminates after for 2 weeks, and records the disease index of each group mouse in 2 weeks, the evaluation method of disease index
As shown in table 2, evaluation result is as shown in table 3.Each group mouse is put to death after experiment and dissects each group mouse, is taken out small
The tumor mass of mouse colon is weighed, and calculates tumor control rate according to following formula, the results are shown in Table 3：
Tumor control rate (%)=2 average knurl weight of (average knurl weight of 2 average knurl weight of control group-to be evaluated group)/control group ×
100%
Wherein, described to be evaluated group refer to the high dose group, middle dose group, low dose group, control group 1, control group 3,
Control group 4 and control group 5.
Table 2
| Score | Weight loss (%) | Stool hardness | It has blood in stool/occult blood | Depilation |
| 0 | - | Normally | Normally | Normally |
| 1 | 1-5 | Nothing | Nothing | Nothing |
| 2 | 5-10 | Loosely | Occult blood | Slightly |
| 3 | 11-15 | Loosely | Occult blood | Moderate |
| 4 | >15 | Watery stool | Bleeding | Seriously |
Table 3
| Disease index | Tumor control rate (%) | |
| High dose group | 2 | 72.84 |
| Middle dose group | 5 | 65.63 |
| Low dose group | 7 | 53.59 |
| Control group 1 | 16 | 27.20 |
| Control group 2 | 16 | - |
| Control group 3 | 11 | - |
| Control group 4 | 13 | - |
| Control group 5 | 14 | - |
| Normal group | 0 | - |
It can be seen that from the result in table 3 and held using cordycepin and mouse of the chemotherapeutics synergistic treatment with colon cancer
Find that the tumor control rate of mouse can reach 53.59-72.84%, specifically, use high agent of the present invention after 2 weeks continuous
When the cordycepin of amount, tumor control rate 72.84%；Using middle dosage of the present invention cordycepin when, tumor control rate
It is 65.63%；Using low dosage of the present invention cordycepin when, tumor control rate 53.59%.And in the same terms
Under, when the mouse of control group 1 only receives chemotherapy without the use of cordycepin, the tumor control rate of mouse is only 27.20%.And it will
The result of control group 3, control group 4 and control group 5 can be with when being compared respectively with high dose group, middle dose group and low dose group
Find out, the mouse with colon cancer only receives the cordycepin of high dose of the invention, middle dosage and low dosage without being carried out at the same time
When chemotherapy, the tumor control rate abiology meaning of mouse, the effect much uses cordycepin and change not as good as the collaboration of the present invention
The effect of drug is treated, the present embodiment illustrates that the cordycepin of the present invention and the drug for the treatment of colon cancer have association from animal level
Same-action.
Embodiment 3
The present embodiment illustrates that cordycepin of the present invention is preparing the medicine with radiotherapy synergistic treatment colon cancer in animal level
Application in object, in particular：
Modeling method is in the same manner as in Example 2.
It takes 80 (18-20g) model of colon cancer mouse to be grouped (every group of 10 mouse) at random, is respectively designated as high dose and puts
Treatment group, middle dosage combination radiotherapy group, low-dose radiotherapy group, the non-combination radiotherapy group of high dose, the non-combination radiotherapy group of middle dosage, the non-combination radiotherapy group of low dosage,
Combination radiotherapy group and control group, it is as follows to the disposition of each group mouse：
High dose radiotherapy group：During mouse receives radiotherapy, each in the morning, afternoon and evening daily primary to give experiment mice gavage 50 micro-
The cordycepin aqueous solution of 90mg/kg weight is risen, and 2 weeks after continuing to last time radiotherapy；
Middle dosage combination radiotherapy group：During mouse receives radiotherapy, each in the morning, afternoon and evening daily primary to give experiment mice gavage 50 micro-
The cordycepin aqueous solution of 60mg/kg weight is risen, and 2 weeks after continuing to last time radiotherapy；
Low-dose radiotherapy group：During mouse receives radiotherapy, each in the morning, afternoon and evening daily primary to give experiment mice gavage 50 micro-
The cordycepin aqueous solution of 30mg/kg weight is risen, and 2 weeks after continuing to last time radiotherapy；
The non-combination radiotherapy group of high dose：The daily primary worm for giving 50 microlitres of 90mg/kg weight of experiment mice gavage each in the morning, afternoon and evening
Careless element aqueous solution, duration are identical as the duration of High dose radiotherapy group；
The non-combination radiotherapy group of middle dosage：The daily primary worm for giving 50 microlitres of 60mg/kg weight of experiment mice gavage each in the morning, afternoon and evening
Careless element aqueous solution, duration are identical as the duration of middle dosage combination radiotherapy group；
The non-combination radiotherapy group of low dosage：The daily primary worm for giving 50 microlitres of 30mg/kg weight of experiment mice gavage each in the morning, afternoon and evening
Careless element aqueous solution, duration are identical as the duration of low-dose radiotherapy group；
Combination radiotherapy group：It is each in the morning, afternoon and evening daily once to give experiment mice gavage 50 microlitres of water during mouse receives radiotherapy；
Control group：It is not processed, gives modeling mouse diet；
Wherein, the specific method is as follows for radiotherapy：
Irradiation condition：Philips deep X-ray therapy machines, voltage 200kV, electric current 100mA, filtering plate 0.5mmCu+
1.0mmAl, daily whole body uniform irradiation 2.0Gy (dosage rate 0.44Gy/min), prolonged exposure 7 days as one therapeutic course.
The disease index of each group mouse in experimentation is recorded, the evaluation method of disease index is as shown in table 2, evaluation knot
Fruit is as shown in table 4.Each group mouse to be put to death after experiment and dissects each group mouse, the tumor mass for taking out mouse Colon is weighed,
Tumor control rate is calculated according to following formula, the results are shown in Table 4：
Tumor control rate (%)=(to be evaluated group of average knurl weight of control group average knurl weight -)/control group average knurl weight ×
100%
Wherein, described to be evaluated group refers to the High dose radiotherapy group, middle dosage combination radiotherapy group, low-dose radiotherapy group, high agent
Measure the non-combination radiotherapy group of non-combination radiotherapy group, middle dosage, the non-combination radiotherapy group of low dosage and combination radiotherapy group.
Table 4
It can be seen that from the result in table 4 for 2 weeks using cordycepin and mouse of the radiotherapy synergistic treatment with colon cancer
Find that the tumor control rate of mouse can reach 71.94-86.51% afterwards, moreover, being suffered from using cordycepin and radiotherapy synergistic treatment
When the mouse of colon cancer, mouse disease index during receiving radiotherapy is low, and activity is also normal, and without death condition, this says
The immunocompetence of mouse can significantly be enhanced when the bright mouse for suffering from colon cancer using cordycepin and radiotherapy synergistic treatment.And only
When using cordycepin, the tumor control rate abiology meaning of mouse, and the activity of mouse and feed are reduced, or even occur
Death condition；When suffering from the mouse of colon cancer only with radiotherapy in the treatment, the disease index of mouse is higher in experimentation, and
And the activity of mouse and feed are reduced, or even there is death condition.Especially individual combination radiotherapy group mouse is entire real
It tests all dead in the period.The present embodiment illustrates that the cordycepin of the present invention can be with radiotherapy synergistic treatment knot from animal level
Intestinal cancer.
Comparative example 1
This comparative example is carried out using method described in embodiment 3, the difference is that being extracted with cordyceps sinensis in this comparative example
Cordycepin in liquid alternative embodiment 3, remaining is in the same manner as in Example 3.
Cordyceps extracting liquid obtains by the following method：
500 milliliters of 50 grams of the stroma of Cordyceps militaris manually cultivated plus water, pressurization are boiled 10 minutes, and salmon pink liquid is obtained,
Supernatant is poured out, adds 200 milliliters of repetitions of water to extract primary.Filter and remove residue merges extracting solution, and is concentrated under reduced pressure.The liquid
Body is in salmon pink, taste fragrance, slightly sweet taste.Cordycepin is a concentration of in the cordyceps extracting liquid obtained with visible Spectra Analysis on Edge Recycling
35 μ g/mL, a concentration of 9.8mg/mL of Cordyceps sinensis polysaccharide.It is configured to high dose solution (cordycepin and Cordyceps sinensis polysaccharide total concentration respectively
For 360 μ g/mL), middle dosage solution (cordycepin and Cordyceps sinensis polysaccharide total concentration be 240 μ g/mL) and low dosage solution (cordycepin and
Cordyceps sinensis polysaccharide total concentration is 120 μ g/mL).
Experimental result is as shown in table 5.
Table 5
The preferred embodiment of the present invention has been described above in detail, still, during present invention is not limited to the embodiments described above
Detail can carry out a variety of simple variants to technical scheme of the present invention within the scope of the technical concept of the present invention, this
A little simple variants all belong to the scope of protection of the present invention.
It is further to note that specific technical features described in the above specific embodiments, in not lance
In the case of shield, can be combined by any suitable means, in order to avoid unnecessary repetition, the present invention to it is various can
The combination of energy no longer separately illustrates.
In addition, various embodiments of the present invention can be combined randomly, as long as it is without prejudice to originally
The thought of invention, it should also be regarded as the disclosure of the present invention.
Claims (5)
1. application of the cordycepin with radiotherapy in the drug for preparing synergistic treatment colon cancer, wherein the cordycepin has formula (1)
Shown in structure, wherein in the drug containing the cordycepin, the cordycepin be unique active constituent；
2. application according to claim 1, wherein the irradiation dose of the radiotherapy is 0.1Gy to 100Gy.
3. application according to claim 1, wherein the drug containing the cordycepin is receiving in the radiotherapy period, connecing
In 1-180 days before by the period of radiotherapy and at least one period in 1-180 days after receiving the period of radiotherapy
Interior use.
4. application according to claim 3, wherein the drug containing the cordycepin within the period for receiving radiotherapy,
It is used in 1-100 days before the period for receiving radiotherapy and in 1-150 days after receiving the period of radiotherapy.
5. application according to claim 1, wherein patient's relative to the drug to be used containing the cordycepin is every
The dosage of kg weight, the drug containing the cordycepin is 0.001-1000mg.
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| CN106822169B (en) * | 2017-01-22 | 2020-08-21 | 中国人民解放军第三军医大学 | Application of cordycepin in preparation of medicine for preventing and/or treating radiation injury |
| CN107412249A (en) * | 2017-08-30 | 2017-12-01 | 上海交通大学医学院附属第九人民医院 | Cordycepin is preparing the application in suppressing tumour medicine |
| CN107898803A (en) * | 2017-11-23 | 2018-04-13 | 广东省微生物研究所 | Application of the cordycepin in anti-trioxypurine medicine is prepared |
| CN109406764B (en) * | 2018-09-13 | 2022-02-01 | 中国辐射防护研究院 | Establishment and evaluation method of in-vivo process evaluation animal model of drug after abdominal cavity radiotherapy |
| CN109439723A (en) * | 2018-11-30 | 2019-03-08 | 王瑞明 | A kind of toxotest method of multi-layer nano compound particle |
| CN117137932B (en) * | 2023-10-18 | 2024-04-19 | 中国中医科学院中药研究所 | Chinese herbal compound preparation for tumors and application thereof |
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